Persistent pulmonary hypertension of the newborn (PPHN) results in significant morbidity and mortality in otherwise normal term infants. Safe, effective therapies for PPHN will only be possible when they can be directed toward the specific defects producing this condition. In this review, the authors discuss three different categories of mediators that may play a role in the normal transition at birth and in the pathophysiology seen in PPHN: (1) lipid mediators, (2) the peptide endothelin, and (3) the oxidant radical, nitric oxide. The potential of using the last mediator, nitric oxide, as a treatment for PPHN is under intensive investigation and is discussed in the final section.